: Neuronal death takes place in the mammalian brain not only as a result of pathological conditions such as epilepsy, Alzheimer's disease, and ischemia, but as well during the normal processes of development. One region of the adult brain in which selective neuronal degeneration and death have been particularly well documented is the hippocampus, the structure in which spatial learning. and memory are consolidated. This neuronal death, which can be induced experimentally, is thought to represent an exaggerated form of the processes normally involved in plasticity and synaptic reorganization. Recent work has identified a gene that mediates neuronal degeneration. This gene, tissue plasminogen activator (tPA), encodes a serine protease expressed in the hippocampus that becomes transcriptionally activated very rapidly after excitotoxin-induced seizure or electrical stimulation. This increase in tPA expression is followed by degeneration and death of the hippocampal neuronal cells. In mutant mice lacking a functional tPA gene, the hippocampal neuronal cells are resistant to such excitotoxin-induced degeneration/death. tPA is also suspected to be involved in normal functioning during learning, memory, and general synaptic plasticity events. Although tPA is synthesized basally by neurons in some regions of the brain and peripheral nervous system, the rapid rise in hippocampal tPA upon injury appears to derive primarily from microglial cells. In addition, microglial cells normally become "activated" during events that lead to neuronal death; however, microglial cells in tPA-deficient mice demonstrate only limited activation. Taken together, the (and other) observations suggest that neuronal degeneration results from a coordinated multicellular process. Our current understanding of tPA's role raises a number of direct and immediately addressable questions: What cellular interactions are required to elicit neuronal degeneration? What signals regulate tPA's synthesis and secretion? The proteolytic nature of the tPA gene product suggests a direct means by which tPA might mediate neuronal degeneration; what substrates does tPA act on? What other genes are required in the pathway? And finally, how can tPA be used to extend our knowledge of the molecular basis of neuronal degeneration and microglial activation?